Mitochondrial signals in the bloodstream: Peripheral signature of mitochondrial dysfunction in mental health. A systematic review

Psychiatric disorders are characterized by marked clinical heterogeneity, overlapping symptom dimensions, and the persistent lack of objective biomarkers. Liquid biopsy has emerged as a promising, non-invasive strategy to identify peripheral molecular signatures that may inform diagnosis and treatment monitoring. Given the central involvement of mitochondrial dysfunction in psychiatric pathophysiology, circulating cell-free mitochondrial DNA (ccf-mtDNA) has attracted increasing interest as a candidate biomarker. Following PRISMA 2020 guidelines, this systematic review synthesized evidence on ccf-mtDNA alterations in bipolar disorder (BD), depressive disorders (DD), and schizophrenia (SCZ). Findings in BD were heterogeneous: several studies reported elevated ccf-mtDNA, particularly in unmedicated individuals and those with cognitive deficits, whereas others observed no differences or even decreased levels compared with healthy controls (HC). In DD, evidence more consistently indicated increased ccf-mtDNA, especially in unmedicated or late-life depression, where higher levels correlated with symptom severity, frailty, and inflammatory indices. These data support ccf-mtDNA as a peripheral marker of mitochondrial and inflammatory dysregulation in DD. Conversely, most studies in SCZ reported no significant differences relative to HC; however, elevated ccf-mtDNA levels observed in cognitively impaired subgroups and in patients exhibiting alterations in brain bioenergetics point to underlying clinical and biological heterogeneity. Collectively, current evidence implicates ccf-mtDNA as a putative biomarker of mitochondrial dysfunction in psychiatry, with greater translational potential in DD and BD. Nonetheless, methodological heterogeneity, small sample sizes, and cross-sectional designs underscore the need for standardized, longitudinal investigations to establish its diagnostic and prognostic validity.